In this era of oxaliplatin-based adjuvant therapy, the optimal sequence in which chemoradiotherapy should be administered for pathological stage N2 rectal cancer is unknown. The aim of this study was to investigate this sequence.
Trang 1R E S E A R C H A R T I C L E Open Access
Patients with pathological stage N2 rectal
cancer treated with early adjuvant
chemotherapy have a lower treatment
failure rate
Yan-Ru Feng, Jing Jin*, Hua Ren, Xin Wang, Shu-Lian Wang, Wei-Hu Wang, Yong-Wen Song, Yue-Ping Liu,
Yuan Tang, Ning Li, Xin-Fan Liu, Hui Fang, Zi-Hao Yu and Ye-Xiong Li
Abstract
Background: In this era of oxaliplatin-based adjuvant therapy, the optimal sequence in which chemoradiotherapy should be administered for pathological stage N2 rectal cancer is unknown The aim of this study was to
investigate this sequence
Methods: In the primary adjuvant concurrent chemoradiotherapy (A-CRT) group (n = 71), postoperative concurrent chemoradiotherapy was administered before adjuvant chemotherapy In the primary adjuvant chemotherapy (A-CT) group (n = 43), postoperative concurrent chemoradiotherapy was administered during or after adjuvant
chemotherapy Postoperative radiotherapy comprised 45–50.4 Gy in 25–28 fractions Concurrent chemotherapy comprised two cycles of oral capecitabine (1,600 mg/m2) on days 1–14 and 22–35 Patients receiving adjuvant chemotherapy with four or more cycles of XELOX (oxaliplatin plus capecitabine) or eight or more cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) were included
Results: Between June 2005 and December 2013, data for 114 qualified rectal cancer patients were analyzed The percentages of patients in whom treatment failed in the A-CRT and A-CT groups were 33.8% and 16.3%,
respectively (p = 0.042) More patients had distant metastases in the A-CRT group than in the A-CT group (32.4% vs 14.3%, p = 0.028) Multivariate analysis indicated that the sequence in which chemoradiotherapy was administered (A-CT vs A-CRT) was an independent prognostic factor for both estimated disease-free survival [hazard ratio (HR) 0
345, 95% confidence interval (CI) 0.137–0.868, p = 0.024] and estimated distant metastasis-free survival (HR 0.366, 95% CI 0.143–0.938, p = 0.036)
Conclusions: In pathological stage N2 rectal cancer patients, administering adjuvant chemotherapy before
chemoradiotherapy led to a lower rate of treatment failure, especially with respect to distant metastasis Adjuvant chemotherapy prescribed as early as possible might benefit this cohort of patients in this era of oxaliplatin-based adjuvant therapy
Keywords: Adjuvant chemoradiotherapy, Adjuvant chemotherapy, Sequence, Rectal cancer
* Correspondence: jingjin201515@sina.com
Department of Radiation Oncology, National Cancer Center/Cancer Hospital,
Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing
100021, China
© The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver
Trang 2Since the pivotal German trial, preoperative
chemoradio-therapy following surgery has been preferred for locally
advanced rectal cancer in the routine practice of most
in-stitutions [1] However, postoperative chemoradiotherapy
and adjuvant chemotherapy are still recommended for
patients with pathological stage II/III disease after
defini-tive surgery without preoperadefini-tive chemoradiotherapy [2]
Among patients with pathological stage N2 rectal cancer
treated with curative intent, about 40% will have distant
metastases and 24% local recurrence at 5 years [3, 4]
Op-timizing the combination of radiotherapy and
chemother-apy is therefore necessary to reduce recurrence Trials
investigating patients with stage II/III rectal cancer
indi-cated that the sequence in which chemoradiotherapy was
administered was not associated with disease-free survival
(DFS), overall survival (OS) or relapse rate [5, 6] However,
there are no reports focusing on pathological stage N2
pa-tients The ADORE trial and the CAO/ARO/AIO-04 trial
indicated the benefit of adjuvant oxaliplatin-based
chemo-therapy for rectal cancer [7, 8] In view of the use of
leucovorin-modulated fluorouracil chemotherapy and the
inclusion of stage II rectal cancer in the previous studies
[5, 6], the aim of the present study was to evaluate the
sequence in which chemoradiotherapy should be
adminis-tered for pathological stage N2 rectal cancer in this era of
oxaliplatin-based adjuvant therapy
Methods
Patients and patient workup
Treatment outcomes were analyzed for pathological stage
N2 rectal cancer patients after curative surgery and the
ad-ministration of differing sequences of adjuvant concurrent
chemoradiotherapy and chemotherapy The inclusion
cri-teria were as follows: 1) postoperative (R0 resection)
patho-logical stage N2 rectal adenocarcinoma; 2) no evidence of
distant metastasis; 3) Karnofsky performance score≥ 70; 4)
receiving postoperative capeciatbine based concurrent
che-moradiotherapy; 5) receiving adjuvant chemotherapy [four
or more cycles of XELOX (oxaliplatin plus capecitabine) or
eight or more cycles of FOLFOX (fluorouracil, leucovorin,
and oxaliplatin)]; 6) no neoadjuvant (chemo) radiotherapy;
7) no pregnancy or lactation; and 8) no previous
malig-nancy or other concomitant malignant disease
In the primary adjuvant concurrent chemoradiotherapy
(A-CRT) group, postoperative concurrent
chemoradiother-apy was administered before adjuvant chemotherchemoradiother-apy In
the primary adjuvant chemotherapy (A-CT) group,
postop-erative concurrent chemoradiotherapy was administered
during or after adjuvant chemotherapy The pretreatment
workup included a complete history and physical
examin-ation, liver and renal biochemical analysis, complete blood
cell count, electrocardiography, carcino-embryonic antigen
determination, abdominal ultrasonography and/or
computed tomography (CT), pelvic CT or magnetic reson-ance imaging (MRI) and chest radiography All patients underwent disease staging using the American Joint Com-mittee on Cancer 2010 staging system
Treatment
Postoperative radiotherapy comprised 45–50.4 Gy (mini-mum photon energy of 6 MV) in 25–28 fractions of 1.8 or 2.0 Gy five times per week over 5–5.5 weeks This dose was delivered using three-field conventional radiotherapy, three-dimensional conformal radiotherapy or intensity-modulated radiotherapy technique The clinical target vol-ume was delineated according to Roels’ guidelines [9], as in previous studies [10–12] Concurrent chemotherapy com-prised two cycles of oral capecitabine (1,600 mg/m2) on days 1–14 and 22–35 Perioperative therapy with XELOX, FOLFOX4 or mFOLFOX6 for a total of 6 months is rec-ommended for patients with stage N2 rectal cancer [2]
Follow-up
Follow-up included physical examination, liver and renal biochemistry, complete blood count, and measurement
of tumor markers every 3 months for the first 2 years, and every 6 months thereafter Abdominal ultrasonog-raphy and/or CT, pelvic CT or MRI and chest radiog-raphy were performed every 6 months Colonoscopic examination was repeated annually Treatment-induced toxicities were scored according to the Common Ter-minology Criteria for Adverse Events version 3.0
Statistical analysis
SPSS version 22.0 (IBM, Armonk, NY, USA) was used for statistical analysis The OS, DFS, locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were measured from the day of surgery to the date of the event Survival data were eval-uated using the Kaplan–Meier method The log-rank test was used in univariate analysis to compare survival outcomes between the A-CRT and A-CT groups Multi-variate analysis using a Cox proportional hazards model was used to test independent significance by backward elimination of insignificant explanatory variables Host factors (age and sex) were included as the covariates in all tests Chi-square, Fisher exact, and Mann–Whitney U tests were used to compare differences between the two groups Statistical tests were based on a two-sided sig-nificance level.p < 0.05 indicated statistical significance
Results
Patient characteristics
Between June 2005 and December 2013, data for 114 rectal cancer patients who met all of the inclusion criteria were analyzed retrospectively Their clinical characteristics are listed in Table 1 There were more
Trang 3patients with stage IIIc disease or tumor deposits in the A-CT group (p < 0.05) Radiation dose did not differ be-tween the two groups However, 93% of patients in the A-CRT group received a full dose of concurrent chemo-therapy, compared with 86% of patients in the A-CT group The median intervals between surgery and the start of adjuvant treatment in the A-CRT and A-CT groups was 6.6 (range 3.6–14.0) weeks and 4.3 (1.9– 16.1) weeks, respectively (p < 0.001) In the A-CT group, the median number of chemotherapy cycles adminis-tered before radiotherapy was four (1–12)
Failure pattern
For all patients, the median local recurrence time was 26.2 (13.4–59.6) months and the median distant metastasis time was 13.8 (6.5–50.0) months The percentages of pa-tients in whom treatment failed in the A-CRT and A-CT groups were 33.8% and 16.3%, respectively (p = 0.042) More patients had distant metastasis in the A-CRT group than in the A-CT group (32.4% vs 14.3%,p = 0.028) The lung (n = 17) was the most common site of distant metas-tasis, followed by the liver (n = 8), the bone (n = 4), non-regional lymph nodes (n = 4), and the peritoneal seeding (n = 3) Details of the patterns of recurrence are shown in Table 2
Survival
The median follow-up time was 34.1 (10.2–112.1) months For all patients, 3-year estimated OS, DFS, LRFS and DMFS rates were 84.6%, 72.5%, 94.8% and 74.1%, respect-ively These rates were 81.8%, 66.7%, 93.7% and 67.5% for patients in the A-CRT group and 90.8%, 83.9%, 97.4% and 86.6% for the A-CT group
Univariate analysis suggested no statistically significant difference in estimated DMFS rate between the A-CRT group and the A-CT group; however, the 3-year esti-mated DMFS in the A-CRT group was higher (86.6% vs 67.5%, p = 0.074) (Fig 1a) No statistically significant
Table 1 Clinical characteristics of 114 patients with pathological
stage N2 rectal cancer
(n = 71)
A-CT group (n = 43)
p
Low anterior resection 54 (76.1) 35 (81.4)
Abdominoperineal resection 17 (23.9) 7 (16.3)
Time to adjuvant treatment (wk) <0.001
Table 1 Clinical characteristics of 114 patients with pathological stage N2 rectal cancer (Continued)
Time to adjuvant radiotherapy (wk) <0.001
Time to adjuvant chemotherapy (wk)
<0.001
Abbreviations: A-CRT primary adjuvant concurrent chemoradiotherapy, A-CT primary adjuvant chemotherapy
Trang 4difference was observed in estimated LRFS, DFS or OS
between the A-CRT and the A-CT groups (Fig 1b, c, d)
Multivariate analysis was performed to adjust for
vari-ous prognostic factors The following parameters were
included in the Cox proportional hazards model: age,
gen-der, distance from anal verge, lymphovascular invasion,
tumor deposits, number of nodes retrieved, number of
positive nodes, time to adjuvant treatment, TNM stage
and the sequence in which chemoradiotherapy was
administered (A-CT vs A-CRT) The sequence of chemo-radiotherapy was identified as an independent prognostic factor for both estimated DFS [hazard ratio (HR) 0.345, 95% confidence interval (CI) 0.137–0.868, p = 0.024] and estimated DMFS (HR 0.366, 95% CI 0.143–0.938, p = 0.036) The outcomes are shown in Tables 3 and 4
Discussion
The findings of this study demonstrate lower treatment failure and better survival (DFS and DMFS) rates when adjuvant chemotherapy was administered first in patients with pathological stage N2 rectal cancer
With improvements in radiotherapy and surgery, re-gardless of whether the patient receives preoperative or postoperative chemoradiotherapy, the incidence of locore-gional recurrence is relatively low; however, distant metas-tasis has become the predominant problem, especially in patients with stage N2 disease [3, 4] New chemotherapy regimens have been investigated to reduce the occurrence
of distant metastasis The MOSAIC trial indicated that adding oxaliplatin to fluorouracil-based adjuvant chemo-therapy significantly improved 5-year DFS and 6-year OS
in stage II/III colon cancer, especially in stage III disease [13] Although the MOSAIC trial did not include rectal cancer patients, oxaliplatin-based adjuvant chemotherapy was still recommended for rectal cancer in the National
Table 2 Failure patterns of patients with pathological stage N2
rectal cancer in A-CRT group and A-CT group
Sites of recurrence A-CRT group A-CT group p
Total no of recurrence 24 33.8 7 16.3 0.042
No of locoregional recurrence 4 5.6 1 2.3 0.647
No of distant metastasis 23 32.4 6 14.3 0.028
All site of distant metastasis
Abbreviations: A-CRT primary adjuvant concurrent chemoradiotherapy, A-CT
primary adjuvant chemotherapy
Fig 1 Kaplan –Meier curves of patients with pathological stage N2 rectal cancer treated with primary adjuvant concurrent chemoradiotherapy (A-CRT)
or primary adjuvant chemotherapy (A-CT) a The 3-year distant metastasis-free survival rates are 67.5% in the A-CRT group and 86.6% in the A-CT group (p = 0.074) b The 3-year locoregional recurrence-free survival rates are 93.7% in the A-CRT group and 97.4% in the A-CT group (p = 0.629) c The 3-year disease-free survival rates are 66.7% in the A-CRT group and 83.9% in the A-CT group (p = 0.153) d The overall survival rates are 81.8% in the A-CRT group and 90.8% in the A-CT group (p = 0.378)
Trang 5Comprehensive Cancer Network guideline [2] Despite no
head to head comparison in the adjuvant setting, current
treatment guidelines accept either XELOX or FOLFOX as
standard of care treatment options [2] Randomized phase
III studies indicated that XELOX is noninferior to
FOL-FOX as a first-line treatment for metastatic colorectal
cancer [14, 15] Most of the support for use of
FOL-FOX or XELOX as adjuvant chemotherapy in rectal
cancer is an extrapolation from the data available for
colon cancer [13, 16, 17] The trial [18] investigating
the efficacy and safety of substituting fluorouracil
with capecitabine for perioperative treatment in
lo-cally advanced rectal cancer indicated that 5-year
overall survival in the capecitabine group was
non-inferior to that in the fluorouracil group The authors concluded that capecitabine could replace fluorouracil
in adjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer
In a meta-analysis of the optimal interval between sur-gery and initiation of adjuvant chemotherapy in colorectal cancer, a 4-week increase in the time to adjuvant chemo-therapy was associated with a significant decrease in both
OS (HR 1.14, 95% CI, 1.10–1.17) and DFS (HR 1.14, 95%
CI, 1.10–1.18) [19] Furthermore, in the study of Kusters
et al., adjuvant chemotherapy prevented local recurrence
in patients with locally advanced rectal cancer [20]
So far, there have been two trials in rectal cancer evaluating treatment outcomes in relation to the se-quence of adjuvant treatment [5, 6] In a prospective randomized trial, 308 patients with resected stage II/III rectal cancer were randomly assigned to receive pelvic irradiation at either the first or the third course of leucovorin-modulated 5-fluorouracil chemotherapy [5]
In the preliminary results, a significantly higher DFS rate was achieved in the early pelvic radiotherapy group (81%
vs 70% at 4 years, p = 0.047) [21] However, no signifi-cant difference in DFS, OS or relapse rate was observed between the two groups after a median follow-up period
of 121 months In the study of Kim et al., 5-year treat-ment outcomes were not significantly influenced by the sequence of adjuvant treatment [6]
In the present study, we focused on stage N2 patients who were more likely to develop distant metastases and local recurrence Only patients receiving adjuvant chemotherapy (four or more cycles of XELOX or eight
or more cycles of FOLFOX) were included to ensure the dose of adjuvant chemotherapy More than 90% of patients in both groups had received a full dose of radi-ation, regardless of whether it was prescribed immedi-ately after R0 resection or after adjuvant chemotherapy With oxaliplatin adjuvant chemotherapy, the whole group exhibited high 3-year estimated OS, DFS, LRFS and DMFS rates (84.6%, 72.5%, 94.8% and 74.1%, respectively) Regarding the relationship between the timing of adjuvant radio/chemoradiotherapy and local recurrence, a systematic review indicated that the risk
of local recurrence increased with waiting time for radiotherapy and the increase in local recurrence rate may translate into reduced survival in some clinical situations However, patients with rectal cancer were not included in this review [22] In our study, the in-cidence of locoregional recurrence was relatively low
in both the A-CRT and the A-CT groups (5.6% and 2.3%, respectively) regardless of whether concurrent chemoradiotherapy was administered early or was delayed However, whether adjuvant chemotherapy is given early or late does matter with regard to distant metastasis and overall recurrence After adjusting for
Table 3 Univariate analysis of prognostic factors for 114
patients with stage N2 rectal cancer
Sex
Men 73 86.0 0.983 75.1 0.831 95.3 0.980 73.9 0.970
Age(years)
<60 91 86.5 0.533 71.1 0.280 95.2 0.943 73.0 0.321
Distance from anal verge (cm)
≤ 5 36 81.8 0.884 65.0 0.247 92.5 0.756 68.0 0.364
pT category
T2 7 100.0 0.223 68.6 0.908 100.0 0.744 68.6 0.892
TNM stage
IIIB 55 88.6 0.262 72.9 0.675 97.4 0.143 71.4 0.845
Lymphovascular invasion
No 86 85.8 0.124 78.2 0.013 93.4 0.819 80.2 0.027
Tumor deposits
No 91 88.7 0.008 75.3 0.258 96.4 0.190 74.3 0.517
Number of nodes retrieved
<12 10 77.8 0.066 36.0 0.002 100.0 0.446 36.0 0.001
Sequence
A-CRT 71 81.8 0.379 66.7 0.153 93.7 0.629 67.5 0.074
Abbreviations: OS overall survival, DFS disease-free survival, DMFS distant
metastasis-free survival, A-CRT primary adjuvant concurrent
chemoradiother-apy, A-CT primary adjuvant chemotherapy
Trang 6confounding factors with a Cox proportional hazards
model, we found that giving adjuvant chemotherapy
before concurrent chemoradiotherapy (CT vs
A-CRT) was a favorable prognostic factor for estimated
DFS and DMFS Given no significant difference in
locoregional recurrence between the A-CRT group
and the A-CT group in our study, we prefer to
ad-minister adjuvant chemotherapy before concurrent
chemoradiotherapy after definitive surgery in
patho-logical stage N2 rectal cancer patients
There is a growing interest in developing neoadjuvant
chemotherapy for locally advanced rectal cancer In a
phase 2, non-randomised trial of locally advanced rectal
cancer, 25 (38%, 27-51) of 65 achieved a pathological
complete response by adding 6 cycles of mFOLFOX6
between chemoradiation and surgery [23] Recently, a
randomized phase 3 trial indicated perioperative
mFOL-FOX6 alone had inferior results and a lower pCR rate
than chemoradiotherapy but led to a similar
downsta-ging rate as fluorouracil-radiotherapy, with less toxicity
and fewer postoperative complications [24] A phase 3
trial (NCT02533271) of comparing effectiveness of
short-term radiotherapy plus neoadjuvant chemotherapy
with preoperative long-term chemoradiotherapy in
lo-cally advanced rectal cancer is undergoing in our center
There are several limitations to the present study,
including the retrospective nature of the study
design and the limited number of patients in the
two groups Furthermore, we did not determine the
optimal time for intervention with radiotherapy A
further prospective randomized study is necessary
for accurate evaluation of the sequence in which
chemoradiotherapy should be administered after
pri-mary surgery in patients with stage N2 rectal cancer
However, conducting such a randomized controlled
trial will be difficult because, since publication of the
German trial, a larger number of patients with
lo-cally advanced rectal cancer have been treated with
preoperative chemoradiotherapy than with
postopera-tive chemoradiotherapy [1]
Conclusions
In pathological stage N2 rectal cancer patients, adminis-tering adjuvant chemotherapy before chemoradiotherapy led to a lower rate of treatment failure, especially with respect to distant metastasis Adjuvant chemotherapy pre-scribed as early as possible might benefit this cohort of patients in this era of oxaliplatin-based adjuvant therapy
Abbreviations
A-CRT: Primary adjuvant concurrent chemoradiotherapy; A-CT: Primary adjuvant chemotherapy; CI: Confidence interval; CT: Computed tomography; DFS: Disease-free survival; DMFS: Distant metastasis-free survival;
FOLFOX: Fluorouracil, leucovorin, and oxaliplatin; HR: Hazard ratio;
LRFS: Locoregional recurrence-free survival; MRI: Magnetic resonance imaging; OS: Overall survival; XELOX: Oxaliplatin plus capecitabine Acknowledgments
None.
Funding This work was supported by grants from the National Natural Science Foundation [No 81272510]; the Wu Jieping Medical Foundation [No 320.6750.10074]; and Beijing Hope Run Special Fund [LC2007A17].
Availability of data and materials Our data can not be made publicly available for ethical reasons Data are from the present study whose authors may be contacted at jingjin1025@163.com or Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Authors ’ contributions Conceived and designed the experiments: JJ ZY YL Performed the experiments: YF JJ HR XW SW WW YS YL YT NL XL HF ZY YL Analyzed the data: YF JJ HR XW YS YL YT NL XL YL Contributed reagents/materials/ analysis tools: YF JJ HR XW SW WW YS YL YT NL XL HF ZY YL Wrote the paper: YF JJ YL Gave many suggestions in the formation of the manuscript:
JJ ZY YL All authors have read and approved the final manuscript, and ensure that this is the case.
Competing interests All authors declared that they have no competing interest.
Consent for publication Not applicable.
Ethics approval and consent to participate This study obtained approval from the Independent Ethics Committee of the Cancer Hospital, Chinese Academy of Medical Sciences to identify patients diagnosed with rectal cancer in our center Because this was a retrospective study, consent was not obtained and patient records were anonymized and de-identified before analysis.
Table 4 Multivariate analysis of prognostic factors for 114 patients with stage N2 rectal cancer
Abbreviations: OS overall survival, DFS disease-free survival, DMFS distant metastasis-free survival, A-CRT primary adjuvant concurrent chemoradiotherapy, A-CT pri-mary adjuvant chemotherapy, HR hazard ratio, CI confidence interval
Trang 7Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Received: 31 March 2016 Accepted: 4 March 2017
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